We showed that COX-1 KO mice have a significant reduction in the cerebral inflammatory response and oxidative damage after LPS. The protection can be attributed to attenuation of microglial activation, a critical process in the initiation of inflammation, and to reduction of inflammatory mediators such as PGE2, IL-1beta, TNF-alpha, and of protein oxidation, a critical factor contributing to the secondary progression of the inflammatory reaction and oxidative damage. Translocation and activation of nuclear factor-kappaB (NF-kB) and signal transducer s and activators of transcription 3 (STAT3), important factors for signaling events during an inflammatory response, were also reduced in COX-1 KO mice. In contrast, the LPS-induced expression of pro-inflammatory cytokines and reactive oxygen species-generating enzymes, such as iNOS and NADPH oxidase, was also increased in COX-2 KO compared to WT mice. These results suggest that COX-1 plays an important role in the regulation of microglial inflammatory response in the central nervous system and COX-1 inhibition might be beneficial to reduce the effects of neuroinflammation and related oxidative stress. These results also imply that selective COX-2 inhibition may worsen neuroinflammatory response.